Respiration involves the introduction of fresh gases, especially oxygen, to the lung during inspiration and the removal of waste gases, particularly carbon dioxide, during expiration. In healthy individuals respiration is normally effected by spontaneous ventilation or breathing which results in the introduction of the necessary gases. Unfortunately, a number of physiological and pathological processes may compromise normal pulmonary function leading to the inhibition of effective respiration or total respiratory failure. In such cases respiratory therapy, often involving artificial ventilation to some degree, is indicated. For example, respiratory therapy is often indicated for patients undergoing surgery or those suffering disorders and diseases of the pulmonary air passages. In particular, patients suffering from lung contusion, diver's lung, post-traumatic respiratory distress, post-surgical atelectasis, irritant injuries, septic shock, multiple organ failure, Mendelssohn's disease, obstructive lung disease, pneumonia, pulmonary edema or any other condition resulting in lung surfactant deficiency or respiratory distress are strong candidates for respiratory therapy. Typically, such respiratory therapy involves the use of mechanical ventilators.
Mechanical ventilators are simply clinical devices that effect ventilation or, in other words, cause airflow into the lungs. More specifically, such devices typically force air into the lungs during the inspiration phase of the breathing cycle but allow a return to ambient pressure during spontaneous exhalation. The forced influx of fresh air by mechanical ventilation facilitates the pulmonary mediated processes that comprise respiration in mammals. One of these processes, removal of waste gases, is a primary mechanism by which carbon dioxide is excreted from the body. In normal gas mediated carbon dioxide removal, fresh air is brought into contact with the alveoli (alveolar ventilation) thereby promoting gas exchange wherein carbon dioxide passes from the body and is exhaled. The other essential bioprocess, oxygenation, comprises the absorption of oxygen into the blood from the lungs. It is primarily a function of the mechanism whereby the partial pressure of oxygen (PO.sub.2) in pulmonary capillary blood equilibrates with the partial pressure of oxygen in inflated alveoli. The oxygen gradient between alveolus and capillary favors transfer of oxygen into blood because the repeated influx of fresh oxygen through ventilation (spontaneous or assisted) maintains alveolar PO.sub.2 at higher levels than capillary PO.sub.2. Modern mechanical ventilators are designed to provide ventilation by regulating tidal volume (breath), flow rate, delivery profile and respiratory flow thereby controlling carbon dioxide excretion. Because they can also regulate airway pressure and the concentration of inspired oxygen they offer control over oxygenation as well.
At least twenty makes and models of mechanical ventilators are used in North America today. Almost all the ventilators used in operating rooms, recovery rooms and intensive care units are volume-controlled ventilators. With a device of this type the operator may set tidal volume, respiratory rate, and inspiratory rate allowing the ventilator to deliver a set volume of gas regardless of the airway pressure. Such devices usually have a pressure cutoff to prevent damage to the lungs. In contrast, pressure-controlled ventilators are standard in neonatal intensive care, in chronic ventilator management and during patient transport. Pressure-controlled ventilators typically allow the operator to select the respiratory rate, the inspiratory gas flow and the peak airway pressure. The ventilator then delivers inspired gas, while monitoring the tidal volume, until the desired pressure is reached. Each of these types of mechanical ventilators incorporate a number of sophisticated features which allow unparalleled control over the delivery of gases to the lung. For example, typical mechanical ventilators offer a number of complex delivery profiles designed to optimize the introduction of gases into the lung taking into account the physical state of the patient, therapeutic requirements and the respiration pattern of the patient under different conditions. In order to meet the diverse of patients requiring ventilation therapy, common mechanical ventilators offer several ventilation modes, each having a variety of programmable parameters, offering an almost unlimited versatility. Some common ventilation modes include controlled mechanical ventilation, assist control, intermittent mandatory ventilation, synchronized intermittent mandatory ventilation, continuous positive airway pressure, pressure controlled ventilation, pressure controlled inverse ratio ventilation, pressure support as well as combinations of modes. Unfortunately, in both types of commercially available ventilators the expired gases, including any bioactive agents introduced during inspiration or exhaled pathogenic material, are typically released into the environment during use.
In contrast to standard mechanical ventilation, liquid ventilation is a technique which involves introducing an oxygenated liquid medium into the pulmonary air passages for the purposes of waste gas exchange and oxygenation. Essentially, there are two separate techniques for performing liquid ventilation, total liquid ventilation and partial liquid ventilation. Total liquid ventilation or "TLV" is the pulmonary introduction of warmed, extracorporeally oxygenated liquid respiratory promoter (typically fluorochemicals) at a volume greater than the functional residual capacity of the subject. The subject is then connected to a liquid breathing system and tidal liquid volumes are delivered at a frequency depending on respiratory requirements while exhaled liquid is purged of CO.sub.2 and oxygenated extracorporeally between the breaths. Conversely, partial liquid ventilation or "PLV" involves the use of conventional mechanical ventilation in combination with pulmonary administration of a respiratory promoter capable of oxygenation. As with TLV the respiratory promoter typically comprises fluorochemicals which may be oxygenated extracorporeally prior to introduction. In the instant application the term "liquid ventilation" will be used in a generic sense and shall be defined as the introduction of any amount of respiratory promoter into the lung, including the techniques of both partial liquid ventilation and total liquid ventilation.
The concept of liquid ventilation originated more than thirty years ago when it was shown that animals submerged in a hyperoxygenated respiratory promoter (saline) could breath the liquid and successfully resume gas breathing. For practical purposes liquid ventilation became a viable technique when it was discovered that fluorochemicals could be used as the respiratory promoter. Liquid breathing using oxygenated fluorochemicals has been demonstrated on several occasions. For example, an animal submerged in an oxygenated fluorochemical liquid may exchange oxygen and carbon dioxide normally when the lungs fill with the fluorochemical. Although the work of breathing is increased in total submersion experiments, the animal can derive adequate oxygen for survival by breathing the oxygenated fluorochemical liquid. In particular, it has been established that total liquid ventilation may keep mammals alive for extended periods prior to returning them to conventional gas breathing.
Use of liquid ventilation may provide significant medical benefits which are not available through the use of conventional mechanical ventilators employing a breathable gas. For example, the weight of the respiratory promoter opens alveoli with much lower ventilator pressure than is possible with gas. Additionally, liquid ventilation using fluorochemicals as the respiratory promoter has been shown to be effective in rinsing out congestive materials associated with respiratory distress syndrome. Moreover, liquid ventilation has been shown to be a promising therapy for the treatment of respiratory distress syndromes involving surfactant deficiency or dysfunction. Elevated alveolar surface tension plays a central role in the pathophysiology of the Respiratory Distress Syndrome (RDS) in premature infants and is thought to contribute to the dysfunction in children and adults. Liquid ventilation, particularly using fluorochemicals, is effective in surfactant-deficient disorders because it eliminates the air/fluid interfaces in the lung and thereby greatly reduces pulmonary surface tension. Moreover, liquid ventilation can be accomplished without undue alveolar pressures or impairing cardiac output and provides excellent gas exchange even in premature infants. Other beneficial aspects associated with liquid ventilation include facilitation of pulmonary drug delivery and lung cancer hyperthermia.
Despite the undeniable advantages associated with liquid ventilation, the use of total liquid ventilation as a therapy presents significant complications. TLV requires that tidal breaths of the respiratory promoter be mechanically cycled into and out of the lungs. Unmodified conventional mechanical ventilators, such as those discussed above, will not work in total liquid ventilation procedures. Total liquid breathing in a hospital setting requires dedicated ventilation equipment, currently not available commercially, capable of handling liquids. Moreover, the respiratory promoter must be oxygenated and purged of carbon dioxide extracorporeally, a difficult process requiring specialized equipment and large volumes of oxygen. Further, extracorporeal scrubbing of the respiratory promoter, particularly fluorochemicals, currently results in substantial losses as part of the medium is vaporized during the procedure. In addition, as the respiratory promoter is oxygenated and purged of carbon dioxide outside the body while being cyclically delivered to the lungs, a large and potentially expensive priming volume of respiratory promoter is required to fill the liquid breathing device. Accordingly, capital costs associated with liquid breathing are considerable.
In order to obviate many of these complications, yet still retain the benefits inherent in liquid ventilation, the technique of partial liquid ventilation was developed. Partial liquid ventilation, as described in Fuhrman, U.S. Pat. No. 5,437,272 and published PCT Application No. WO 92/19232, is a safe and convenient clinical application of liquid breathing using oxygenated fluorochemicals. In PLV a liquid, vaporous or gaseous respiratory promoter (again typically a fluorochemical) is introduced into the pulmonary air passages at volumes ranging from just enough to interact with a portion of the pulmonary surface all the way up to the functional residual capacity of the subject. Respiratory promoters are any compound that functions, systemically or pulmonarily, to improve gas exchange and respiration efficiency. Respiratory gas exchange is thereafter maintained for the duration of the procedure by continuous positive pressure ventilation using a conventional open-circuit gas ventilator. Like total liquid ventilation, the pulmonary introduction of the respiratory promoter eliminates surface tension due to pulmonary air/fluid interfaces as well as improving pulmonary function and gas exchange in surfactant deficiency and other disorders of the lung. As PLV does not require extracorporeal oxygenation and scrubbing or the cyclic introduction of the respiratory promoter to the lung, the use of specialized expensive equipment is not required. Rather, well established conventional off-the-shelf ventilators may be used to provide the necessary oxygenation and carbon dioxide purging in vivo. Moreover, as it is predominantly gas rather than liquid that moves in tidal fashion with each breath, the airway pressures required for the procedure may be much lower than during TLV. Thus, the potential for barotrauma is substantially reduced. Finally, when the procedure is over the introduced the liquid, gaseous or vaporous respiratory promoter is simply allowed to evaporate rather than being physically removed as in TLV.
As previously indicated, fluorochemicals are the preferred respiratory promoter for both TLV and PLV. In general, fluorochemicals compatible with liquid ventilation will be clear, odorless, nonflammable, and essentially insoluble in water. Additionally, preferred fluorochemicals are denser than water and soft tissue, have a low surface tension and, for the most part, a low viscosity. In particular, brominated fluorochemicals are known to be safe, biocompatible substances when appropriately used in medical applications. It is additionally known that oxygen, and gases in general, are highly soluble in some fluorochemicals. For example, some fluorochemical liquids may dissolve over twenty times a much oxygen and over thirty times as much carbon dioxide as a comparable amount of water. Oxygenatable fluorochemicals act as a solvent for oxygen. They dissolve oxygen at higher tensions and release this oxygen as the partial pressure decreases. Carbon dioxide behaves in a similar manner. In addition to carrying gases and removing waste products, respiratory promoters such as fluorochemicals may be used as pulmonary drug delivery vehicles, either in conjunction with liquid ventilation or as independent therapy. For example, aerosol delivery systems may rely on a mixture of a therapeutically active agent with one or more respiratory promoters to increase dispersion, efficacy and stability of the bioactive agent. Moreover, selected respiratory promoters, including, in particular, fluorochemicals, have been shown to have pulmonary and systemic anti-inflammatory effects. Accordingly, despite relatively high costs, it is desirable to employ fluorochemicals as the respiratory promoter of choice in current liquid ventilation procedures and pulmonary drug delivery.
While liquid ventilation is a significant improvement over conventional ventilation, the escape of the respiratory promoter, particularly fluorochemicals, into the environment in the form of vapors, compromises the effectiveness of both TLV and PLV therapy. During normal fluorochemical ventilation procedures the generation and release of such vapor may be significant. For example, in current PLV therapy conventional mechanical ventilators release the expired gas, including fluorochemical vapors, into the environment or store them for future disposal. In adult PLV treatments evaporative fluorochemical losses may correspond to approximately 10-20% of functional residual capacity per hour or approximately 400 to 800 grams of fluorochemical per hour. Significant fluorochemical losses also occur during TLV treatments. In this case, the greatest losses occur as the circulated liquid medium is subject to extracorporeal oxygenation and carbon dioxide purging. In particular, a great deal of gaseous oxygen must be introduced into the respiratory promoter to disassociate and purge the accumulated carbon dioxide prior to reintroduction of the respiratory promoter into the body. The majority of the oxygen passes through the respiratory promoter and is vented, carrying with it carbon dioxide and, unfortunately, fluorochemical vapor. Of course, if the therapy is to be continued additional respiratory promoter must be added to maintain effective residual volumes. As fluorochemical liquids and other respiratory promoters suitable for liquid ventilation can be relatively expensive, such losses can substantially raise the cost of such therapies. Moreover, in either type of treatment, the loss of respiratory promoter complicates both dosing regimens and monitoring the current volume of material in the lung.
Besides the loss of expensive material, the use of fluorochemical based respiratory promoters can damage conventional ventilation equipment which incorporate materials that are not compatible. For example, a number of engineering plastics used in current ventilators tend to swell in the presence of fluorochemicals. In other currently used materials, exposure to fluorochemicals will leach plasticizers causing the material to become brittle and subject to failure under much less stress. Further, modern conventional ventilators contain a number of delicate sensors for monitoring the levels and condition of both the inspiratory and respiratory gases. As with the ventilators themselves, many of these sensors incorporate materials that are not fully compatible with fluorochemicals or other potential respiratory promoters. Accordingly, the use of fluorochemicals with conventional systems may lead to a degradation of sensory data and inaccurate readings if the apparatus is not properly monitored and maintained. Such materials problems can be severe, if not fatal, handicaps when trying to gain regulatory approval of a therapeutic method or incorporation of a specific device into a preapproved treatment. Materials problems aside, each different ventilator used for liquid ventilation, including commercially available machines, will likely have to be individually cleared by the Food and Drug Administration prior to use in such treatments. Obtaining such clearance, if possible, can be an expensive and time consuming process that can limit the widespread use of an otherwise proven and effective therapy.
Unfortunately, no effective means of addressing these problems or providing closed-circuit ventilation therapy currently exists. For instance, as indicated above commercially available mechanical ventilators vent, as a matter of course, any beneficial gases or vapors present in the pulmonary air passages along with the waste gases. On the other hand, pulmonary administration devices employing sealed delivery systems lack the necessary versatility and sophisticated delivery ability required for effective ventilation therapy. For example, U.S. Pat. No. 4,928,683 describes a closed line anesthesia respiratory apparatus using multiple fixed volume fluid driven compartments. While delivering precise volumes, this complex fixed delivery system does not provide the sophisticated profiles and versatility necessary for extended ventilation therapy. Moreover, the disclosed apparatus is not modular and compatible with off-the-shelf equipment. Similarly, U.S. Pat. No. 5,119,810 provides a ventilation system driven by a mechanical powered piston. Yet, this system does not allow for the use of existing ventilation apparatus and does not isolate the mechanical components from the respiratory gas. As such, neither of the disclosed devices solve the aforementioned problems. Thus, there still remains a great need for a closed-circuit ventilation system which allows for the isolation and retention of respiratory material.
Accordingly, it is an object of the present invention to provide methods and apparatus for closed-circuit pulmonary ventilation.
It is another object of the present invention to provide methods and apparatus for the efficient retention of a respiratory promoter during partial liquid ventilation.
It is yet another object of the present invention to provide methods and apparatus for the retention of a respiratory promoter during total liquid ventilation.